1. Field of the Invention
The present invention relates to a process for the preparation of 3-amino-2-hydroxypropylphosphinic acid derivatives which are valuable pharmaceutically active ingredients and can be used, for example, as antidepressants.
2. Description of the Art
U.S. Pat. No. 5,300,679, and the articles of Froestl et al., J. Med. Chem. 38, 3297–3312 (1995) and Froestl et al., J. Med. Chem. 38, 3313–3331 (1995), all of which are incorporated herein by reference, disclose that 3-amino-2-hydroxypropylphosphinic acid derivatives possess valuable pharmacological properties such as a binding affinity to GABA (γ-aminobutyric acid) receptors, specifically to the GABAB receptor subtype, and can influence the release of excitatory amino acids and neurotransmission processes in the brain. Accordingly, a few of these compounds, which are antagonists of the GABAB receptor, are useful as pharmaceutically active ingredients for the treatment of disease states of the central nervous system like anxieties, depressions or impaired cognitive functions, i.e., they are useful as nootropic, antidepressive or anxiolytic agents. Of particular interest because of their property profiles are the GABAB receptor antagonists of the formula I in which R is a benzyl group or a cyclohexylmethyl group.

The process for the preparation of a compound which is used as a pharmaceutically active ingredient in a medicament and needed on an industrial scale has to fulfill various requirements. The process and the obtained product have to be in line with the regulatory requirements and have to be reproducible and validated. In particular, regulatory authorities stipulate a precise degree of purity of the obtained drug substance. On the other hand, a process performed on an industrial scale for the preparation of a marketed product should of course be as simple, cost and labor effective as possible. If possible, it should thus avoid the use of expensive starting materials, physiologically unacceptable toxic materials, difficult technical operations, long reaction times, or a large number of procedural steps, for example. In this respect, the known processes for the preparation of compounds of the formula I have considerable drawbacks which render them hardly suitable for a production on a large scale.
In the article of Froestl et al., J. Med. Chem. 38, 3313–3331 (1995) a process for the preparation of hydrochlorides of the racemic compounds of formula I in which R is benzyl or cyclohexylmethyl is disclosed. The method disclosed therein utilizes corrosive starting materials such as chlorotrimethylsilane, which is especially not suitable for a commercial operation. Furthermore, this method involves a number of steps thus rendering it unsuitable for a commercial operation. More importantly, a several of the intermediates formed therein need to be purified by column chromatography before they can be used in the subsequent steps.
Froestl et al., J. Med. Chem. 38, 3313–3331 (1995) also discloses a process for the preparation of enantiomerically pure 3-amino-2-hydroxypropylphosphinic acid derivatives utilizing the appropriate chiral epichlorohydrin. This method also suffers from all of the same problems discussed above. That is, undesirable starting materials such as chlorotrimethylsilane and a need for purifying the intermediates by column chromatography.
Most importantly, several of these processes utilize various other substances which are unsuitable for preparing pharmaceutical grade end-products. For instance, Froestl et al., employ propylene oxide to convert the hydrochloride of the final product to free amine. It is well known that propylene oxide is a known carcinogen and therefore it is beneficial to avoid such materials in the preparation of a pharmaceutically active ingredient. Similarly, a few of these processes utilize solvents which are not advantageous in the preparation of pharmaceutically active compounds, for example, use of solvents such as tetrahydrofuran is undesirable.
Various other drawbacks of these known processes are also evident. For example, several steps in these processes require long reaction times, which lead to a very low time-space yield. The necessity to filter the suspension containing the moisture-sensitive silyl intermediate requires special technical devices and thus increased cost of operation. Thus, there is a need for a simpler and improved process for the production of the compounds of formula I. The present invention satisfies this need by providing such a process.